Intermediate HDL Cholesterol Levels Linked With Better Survival

Researchers found a U-shaped relationship between HDL cholesterol and premature death across all levels of kidney function.

Maintaining an intermediate level of high density lipoprotein cholesterol (HDL-C) may offer the best chances of survival, a new study finds.

Investigators led by Ziyad Al-Aly, MD, FASN, and Benjamin Bowe, MPH, of the Clinical Epidemiology Center at the VA St. Louis Health Care System in Missouri, examined all-cause mortality among 1,764,986 US male veterans with at least a single measurement of estimated glomerular filtration rate (eGFR) and HDL-C between October 2003 and September 2004.

Over 9.1 years of follow up, the most deaths (40.1%) occurred among men with the lowest HDL-C level (25 mg/dL and below). When the team modeled survival using the lowest HDL-C level as a reference, they discovered that intermediate HDL cholesterol levels (between 25 and 50 mg/dL) were associated with lower risks of dying across all levels of eGFR.

Remarkably, the apparent protection eroded for the highest HDL-C level (50 mg/dL and above). Higher death risks, similar to the reference group, were found among men with HDL-C mg/dL 50 mg/dL and above at the highest and lowest eGFR (below 30 mL/min/1.73m2 or 90 mL/min/1.73m2 and above).

“The finding that high HDL-C was also associated with higher risk of death was not expected and has not been reported previously in large epidemiologic studies such as the Framingham Heart Study and others,” Dr Al-Aly stated in a press release. Additional analyses actually revealed a U-shaped curve between HDL cholesterol and early death. “Our findings may explain why clinical trials aimed at increasing HDL-C levels have failed to show improvement of clinical outcomes,” Bowe added.

A lower eGFR reduced some of the benefit of intermediate HDL-C, but the association was still significant. The presence of cardiovascular disease also weakened the association between HDL-C and mortality from any cause.

Findings from previous experimental and pharmaceutical research “…supports the notion that there may be a range of HDL-C values where HDL-C may have a salutary effect, beyond which higher HDL-C may not be beneficial and may be associated with untoward outcomes,” Dr Al-Aly and colleagues remarked in the Clinical Journal of the American Society of Nephrology.

HDL-C may be a surrogate rather than a driver of outcomes, they acknowledged. Men with both low eGFR and low HDL-C, for instance, also had more comorbid conditions. Regardless, HDL-C may be useful for risk assessment.

Among the study's limitations, the investigators noted that they could not assess HDL size, composition, functional capacity, or subclasses. They also could not thoroughly examine cause of death, although cardiovascular causes don't appear to be a major culprit. Cancer risks and inflammation are other possibilities that require investigation. Finally, due to the select population, results may not be generalizable.